内源性Mic60蛋白在心肌肥厚和心力衰竭中作用以及机制研究

Heart failure is frequently preceded by ventricular hypertrophy, and ventricular hypertrophy is a major predictor for progressive heart disease and an adverse prognosis. Mic60 (mitofilin), one of the most abundant proteins in mitochondria, was first found in the heart and was originally described as a heart muscle protein (HMP) because of its abundance in cardiac tissue. We have previously shown that overexpression of Mic60 potentially promotes cardiac hypertrophy in mouse heart, suggesting a possible function for Mic60 in heart disease. However, the role of endogenous Mic60 in cardiac hypertrophy and heart failure remains unclear. Our preliminary data showed that global knockout of Mic60 in mouse led to embryonic lethal. In the present project, both cardiac-specific inducible and heterozygous Mic60 knockout mice will be used to investigate the role of endogenous Mic60 in cardiac pathological processes, including cardiac hypertrophy, inflammation, apoptosis and fibrosis induced by aortic banding (AB) or Angiotensin II infusion. The generation of reactive oxygen species (ROS) and the effects on mitochondrial remolding in response to hypertrophic stimuli will also be investigated in these mice. At the cellular level, isolated primary cardiomyocytes will be used to investigate the underlying molecular mechanism involved in the process of cardiac hypertrophy and failure. Thus, this study will provide new insights into the molecular mechanisms of cardiac hypertrophy and heart failure, and will also provide a potential target for heart failure treatment.

心肌肥厚可以导致心力衰竭，对于心力衰竭的发生起到关键作用。Mic60 (又称mitofilin)蛋白是最先在心脏中被纯化出来的一种表达丰富的线粒体蛋白，本项目前期研究发现心肌细胞中过表达Mic60促进心肌肥厚，但内源性Mic60在心肌肥厚和心力衰竭中作用及机制还不清楚。申请人初步研究发现Mic60的全身敲除导致胚胎致死。本研究运用Mic60可诱导性心脏特异性敲除及Mic60杂合敲除小鼠研究Mic60对主动脉缩窄和血管紧张素II诱导的心肌肥厚、炎症、凋亡和纤维化中作用；阐述其对于活性氧自由基产生和线粒体重塑的影响及其分子机理；进一步在细胞水平，探讨Mic60对心肌细胞肥大、炎症、凋亡以及线粒体重塑等作用及其分子机制。阐明内源性Mic60对心肌肥厚、炎症、凋亡以及纤维化作用的分子机制，为心肌肥厚及其诱导的心衰的防治提供新的防治靶点。

心脏疾病是危害人类生命健康最严重、最普遍的疾病之一。我国心脏疾病的发病率和死亡率呈逐年上升趋势，探索心脏疾病的发病机制具有十分重要的科学价值。而心肌肥厚导致心力衰竭，是评价心脏功能重要的指标。在心肌肥厚的刺激因素作用下，心肌发生重塑，心肌细胞中的线粒体结构和功能的重塑，促进心肌肥厚和心力衰竭的发生。本项目利用线粒体相关蛋白Mic60以及能量代谢相关的SIRTUIN家族（SIRT4, SIRT2）的基因敲除小鼠与转基因小鼠建立的心肌肥厚导致心力衰竭的小鼠模型。研究发现Mic60可能会成为治疗舒张功能障碍相关的心力衰竭的潜在靶点，为进一步探索治疗心血管疾病提供了重要的理论基础。在项目执行过程中进一步深入研究Mic60的组蛋白去乙酰化修饰状态，发现了组蛋白去乙酰化酶SIRT4和SIRT2等在心肌肥厚导致的心力衰竭中的作用以及作用机制，提升了本项目的研究范围和科学意义。本项目按照计划完成任务。研究成果主要以论文形式体现，本项目总体上发表标注项目基金号且申请人为通讯或者第一作者（含并列）SCI文章14篇，其中影响因子大于 10 的研究论文3篇，其中有2篇影响因子大于 20。